CHCHD10 and SLP2 control the stability of the PHB complex: a key factor for motor neuron viability
| Autor: | Emmanuelle C Genin, Sylvie Bannwarth, Baptiste Ropert, Françoise Lespinasse, Alessandra Mauri-Crouzet, Gaelle Augé, Konstantina Fragaki, Charlotte Cochaud, Erminia Donnarumma, Sandra Lacas-Gervais, Timothy Wai, Véronique Paquis-Flucklinger |
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| Přispěvatelé: | Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Biologie mitochondriale – Mitochondrial biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Commun de Microscopie Appliquée (CCMA), Université de Nice Sophia-Antipolis (UNSA), This work was made possible by grants to V.P.-F. from the ANR (Agence Nationale de la Recherche) ANR-16-CE16-0024-01 and from the FRM (Fondation pour la Recherche Médicale) FRM: MND202004011475., We acknowledge Thibault Léger and the Proteomics facility of the Institut Jacques Monod, University of Paris Cité for mass spectrometry analysis. We also thank Christelle Boscagli for technical help. We gratefully acknowledge the IRCAN’s Molecular and Cellular Core Imaging (PICMI) facility, supported financially by FEDER, Conseil régional Provence Alpes-Côte d’Azur, Conseil Départemental 06, Cancéropôle PACA, Gis Ibisa and Inserm, the IRCAN’s Animal core facility, supported by FEDER, Région Provence Alpes-Côte d’Azur, Conseil Départemental 06 and Inserm, the IRCAN’s Histology core facility, supported by Région Provence Alpes-Côte d’Azur, Cancéropôle PACA and Université Côte d’Azur and, the University’s CCMA Electron Microscopy facility supported by Université Côte d’Azur, Région Provence Alpes-Côte d’Azur, Conseil Départemental 06 and Gis Ibisa, ANR-16-CE16-0024,MicroGol,Implication des fonctions sécrétoires de l'appareil de Golgi dans le développement des microcéphalies postnatales avec déficit intellectuel(2016), Lemesle, Marie, Implication des fonctions sécrétoires de l'appareil de Golgi dans le développement des microcéphalies postnatales avec déficit intellectuel - - MicroGol2016 - ANR-16-CE16-0024 - AAPG2016 - VALID |
| Rok vydání: | 2021 |
| Předmět: |
Motor Neurons
PHB = prohibitin Amyotrophic Lateral Sclerosis Membrane Proteins PLA = proximity ligation assay MICOS = mitochondrial contact site and cristae organizing system MESH: Amyotrophic Lateral Sclerosis* / genetics Amyotrophic Lateral Sclerosis* / metabolism Animals Frontotemporal Dementia* / genetics Humans Membrane Proteins* / genetics Membrane Proteins* / metabolism Mice Mitochondria / metabolism Mitochondrial Proteins* / genetics Mitochondrial Proteins* / metabolism Motor Neurons / metabolism Prohibitins Transcription Factors / genetics IMM = inner mitochondrial membrane Mitochondria Mitochondrial Proteins Mice ALS = amyotrophic lateral sclerosis [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie Frontotemporal Dementia Prohibitins motor neuron disease mitochondrion Animals Humans FTD = frontotemporal dementia [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie Neurology (clinical) RC = respiratory chain MN = motor neuron Transcription Factors |
| Zdroj: | Brain-A Journal of Neurology Brain-A Journal of Neurology, 2022, 145 (10), pp.3415-3430. ⟨10.1093/brain/awac197⟩ |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | CHCHD10 is an amyotrophic lateral sclerosis/frontotemporal dementia gene that encodes a mitochondrial protein whose precise function is unclear. Here we show that Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing protein 10 interacts with the Stomatin-Like Protein 2 and participates in the stability of the prohibitin complex in the inner mitochondrial membrane. By using patient fibroblasts and mouse models expressing the same CHCHD10 variant (p.Ser59Leu), we show that Stomatin-Like Protein 2 forms aggregates with prohibitins, found in vivo in the hippocampus and as aggresome-like inclusions in spinal motor neurons of Chchd10S59L/+ mice. Affected cells and tissues display instability of the prohibitin complex, which participates at least in part in the activation of the OMA1 cascade with OPA1 processing leading to mitochondrial fragmentation, abnormal mitochondrial cristae morphogenesis and neuronal death found in spinal cord and the hippocampus of Chchd10S59L/+ animals. Destabilization of the prohibitin complex leads to the instability of the mitochondrial contact site and cristae organizing the system complex, probably by the disruption of OPA1–mitofilin interaction. Thus, Stomatin-Like Protein 2/prohibitin aggregates and destabilization of the prohibitin complex are critical in the sequence of events leading to motor neuron death in CHCHD10S59L-related disease. |
| Databáze: | OpenAIRE |
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